The aim of this project is to explore the role of high dose humoral stimulatory activity (HSA) delivered exogenously on the growth of normal and malignant clonogenic cells to determine if manipulations with HSA both in vivo and in vitro enhance the cytotoxic effect of drugs on malignant cells while increasing the therapeutic index. The use of exogenous HSA as a reagent to substitute of the initial drug in a timed sequence is an extension of the hypothesis long a concern of this laboratory. We have reason to believe that the synergistic therapeutic benefit of timed sequential therapy achieved both in the lab and in the clinic relates to the induction of endogenous HSA by the initial drug which promotes a dose-realated growth stimulus to previously quiescent and thereby protected tumor cells. This enhanced growth of malignant cells increases their sensitivity to cycle-active drugs, while clinically sparing the normal stem cell. Exogenous HSA in marrow mixtures should force maturatin of normal bone marrow elements while stimulating an ongoing proliferation of leukemic cells, resulting in a therapeutic advantage. Studies to develop such principles will be conducted both in vitro and in vivo with manipulations of cell growth and ara-C sensitivity examined in bone marrow mixtures as measured by bioassay in the busulfan (BU) induced aplastic LBN rat, and in the rat bearing leukemia of varied amounts and/or normal bone marrow. In addition to the rat as bioassay, clonogenic assays of rat CFU-c and L-CFU-S will be used. Control reagents and HSA will be obtained from the BU treated rat, long bone conditioned media, and from semi-purified human sera from lectin columns. The ultimate goal is to develop a rationale for the use of HSA in autologous bone marrows in vitro, and in the intact animal with malignancy to increase the therapuetic index of cytotoxic drugs.